Polyamines as antiviral agents in animals

ABSTRACT

AND WHEN X&#39;&#39; is phenylenedimethylene, m is 0; Y is selected from the group consisting of straight chain alkylene of from 2 to 8 carbon atoms and phenylenedimethylene; A is selected from the group consisting of hydrogen, cyano, hydroxy, alkoxy of from 1 to 20 carbon atoms, alkanoyloxy of from 2 to 20 carbon atoms, phenylcarbamoyloxy, chloro, bromo, omega carboxyalkanoyloxy(lower alkyl), alkanoyloxy of from 1 to 6 carbon atoms, carbo(lower alkoxy) and alkanoylthio of from 2 to 20 carbon atoms and alkylthio of from 1 to 20 carbon atoms; R5 is selected from the group consisting of hydrogen, alkyl of from 1 to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (lower alkoxy)lower alkyl and   R6 is selected from the group consisting of hydrogen, alkyl of from 12 to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (lower alkoxy)lower alkyl and   R7 is selected from the group consisting of alkyl of from 12 to 20 carbon atoms and   R8 is selected from the group consisting of alkyl of from 1 to 20 carbon atoms and   each of p and n is 0 or an integer from 1 to 6, with the proviso that the sum of p and n is no greater than 6; and Z is selected from the group consisting of omega -carboxy(lower alkyl), morpholino, piperidino, piperazino, N-( omega -hydroxy lower alkyl)piperazino and N-(lower alkyl)piperazino.   M IS 0 OR 1, WITH THE PROVISOS THAT ONLY ONE OF X and X&#39;&#39; is   X&#39;&#39; is selected from the group consisting of X, phenylenedimethylene and   Ro is alkoxy of from 1 to 18 carbon atoms; EACH OF R&#39;&#39; and R&#39;&#39;&#39;&#39; is selected from the group consisting of hydrogen, alkyl, alkoxy of from 1 to 18 carbon atoms; R&#39;&#39; and R&#39;&#39;&#39;&#39; when taken together are methylenedioxy; PROVIDED THAT THE TOTAL NUMBER OF CARBON ATOMS IN Ro, R&#39;&#39; and R&#39;&#39;&#39;&#39; is from 5 to 48; R3 is selected from the group consisting of hydrogen, alkyl of from 1 to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, phenylcarbamoyloxy(lower alkyl), omega carboxyalkanoyloxy-(lower alkyl), allyl, alkanoyl of from 1 to 6 carbon atoms, alkanoyloxy(lower alkyl), carbo(lower alkoxy)lower alkyl, carboxy(lower alkyl), alkoxy(lower alkyl) and gem-di(lower alkoxy)-lower alkyl; R4 is selected from the group consisting of hydrogen, alkyl of from 1 to 8 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, carbo(lower alkoxy)lower alkyl, alkanoyloxy(lower alkyl), carboxy(lower alkyl), alkoxy(lower alkyl), phenylcarbamoyloxy(lower alkyl), omega -carboxyalkanoyloxy(lower alkyl), allyl, dihydroxyalkyl of from 3 to 8 carbon atoms, and morpholinoethyl; with the proviso that no more than two of the R variables are hydroxyalkyl; R3 and R4 when taken together with the nitrogen to which they are attached are morpholino; X is selected from the group consisting of straight chain alkylene of from 2 to 6 carbon atoms and   R2 is selected from the group consisting of alkyl of from 12 to 20 carbon atoms, aralkyl and aryloxyalkyl of from 12 to 24 carbon atoms and   AND THE NON-TOXIC ACID ADDITION SALTS THEREOF WHEREIN R1 is selected from the group consisting of alkyl of from 1 to 20 carbon atoms, aralkyl, aryloxyalkyl, hydroxyalkyl of from 2 to 8 carbon atoms and   Combating viral infections in vertebrate animals by administering to the animals an amine selected from those having the formulae:

baited States Patent 1191 Cronin et a1.

11] 3,872,171 1 1Mar. is, 1975 Related 1.1.5. Application Data [63]Continuation-in-part of Ser. No. 146,548, May 24, 1971, abandoned, whichis a continuation-in-part of Ser No. 62,192, Aug. 7, 1970, abandoned.

[52] US. Cl .1 260/584 R, 424/250, 424/298, 424/304, 424/311, 260/583 P,260/570.5 P, 260/570.7, 260/340.5, 260/584 R, 260/471 C, 260/518 R,260/584 A [51] Int. Cl. C070 91/12 [58] Field of Search 260/584 R [56]References Cited UNITED STATES PATENTS 2,368,521 1/1945 Clifford et a]260/584 R 2,393,825 l/1946 Senkus 260/584 R 2,541,089 2/1951 Nikawitz260/584 R 2,759,021 3/1956 Gaar et a1. 260/584 R 3,200,153 8/1965Kirkpatrick 260/584 R 3,494,870 2/1970 Kersnar 260/584 R FOREIGN PATENTSOR APPLICATIONS 112,366 12/1965 Netherlands 260/584 R 1,079,597 8/1965United Kingdom.,........,. 260/584 R OTHER PUBLICATIONS Chem. Abstracts2151 Primary Examiner-Lewis Gotts Assistant Errmu'ncw-D, R. PhillipsAttorney, Agent, or Firm-Connolly and Hutz {57] ABSTRACT Combating viralinfections in vertebrate animals by administering to the animals anamine selected from and the non-toxic acid addition salts thereofwherein R is selected from the group consisting of alkyl of from 1 to 20carbon atoms, aralkyl, aryloxyalkyl, hydroxyaikyl of from 2 to 8 carbonatoms and CH2"; n

R is selected from the group consisting of alkyl of from 12 to 20 carbonatoms, aralkyl and aryloxyalkyl of from 12 to 24 carbon atoms and R RIR" CH -3 R" is alkoxy of from 1 to 18 carbon atoms;

each of R and R is selected from the group consisting of hydrogen,alkyl, alkoxy of from 1 to 18 carbon atoms; R and R" when taken togetherare methylenedioxy;

provided that the total number of carbon atoms in R". R and R is from 5to 48;

R isselectecl from the group consisting of hydrogen, alkyl of from 1 to20 carbon atoms, hydroxyaikyl of from 2 to 8 carbon atoms,phenylcarbamoyloxy( lower alkyl), w-carboxyalkanoyloxy-(lower alkyl),allyl, alkanoyl of from 1 to 6 carbon atoms, alkanoyloxy(lower alkyl),carbo(lower alkoxy)lower alkyl, carboxy(1ower alkyl), a1koxy(loweralkyl) and gem-di(1ower alkoxy)-lower alkyl;

R, is selected from the group consisting of hydrogen, alkyl of from 1 to8 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, carbo(loweralkoxy)1ower alkyl, a1kanoy1oxy(1ower alkyl), carboxy(1ower alkyl),alkoxy(lower alkyl), phenyl-carbamoyloxy(lower alkyl),w-carboxya1kanoy1oxy(lower alkyl), allyl, dihydroxyalkyl of from 3 to 8carbon atoms, and morpholinoethyl; with the proviso that no more thantwo of the R variables are hydroxyalkyl;

R and R when taken together with the nitrogen to which they are attachedare morpholino;

X is'selected from the group consisting of straight chain alkylene offrom 2 to 6 carbon atoms and and United States Patent [191 Cronin et al.

[ Mar. 18. 1975 [54] POLYAMINES AS ANTIVIRAL AGENTS IN ANIMALS X isselected from the group consisting of X, phenylene-dimethylene and m isO or I, with the provisos that only one of X and X is O at and when X isphenylenedi methylene, m is 0;

Y is selected from the group consisting of straight chain alkylene offrom 2 to 8 carbon atoms and phenylenedimethylene;

R! R CH -5 R is selected from the group consistingof hydrogen, alkyl offrom 12 to 20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms,(lower alkoxy)lower alkyl and R is selected from the group consisting ofalkyl of from 12 to 20 carbon atoms and R" R is selected from the groupconsisting of alkyl of from 1 to 20 carbon atoms and each ofp and n is0655518 from I :66, withthe proviso that the sum of p and n is nogreater than 6; and

Z is selected from the group consisting of arcarboxyflower alkyl),morpholino, piperidino, piperazino, N-(w-hydroxy lower alkyl)piperazinoand N-( lower alkyl)piperazino.

6 Claims, No Drawings POLYAMINES AS ANTIVIRAL AGENTS IN ANIMALS CROSSRFERENCE To RELATED APPLICATIONS This application is acontinuation-in-part of my copending application Ser. No. 146,548, filedMay 24. 1971, and now abandoned which in turn is a continuation-inpartof my application Ser. No. 62.192. filed Aug. 7, 1970 and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to a novel method forcombating viral infections in vertebrate animals which comprisesadministering to the animals a monoamine, a diamine or a triamine. Moreparticularly, it relates to combating viral infections in vertebrateanimals by parenteral, intranasal or topical administration of asubstituted aliphatic primary amine, a substituted alkanediamine, asubstituted nitrogen-containing heterocyclic compound or a triaminecompound.

The cells of vertebrates produce, in response to virus infection, asubstance which enables cells to resist the multiplication of a varietyof viruses. The viral-resisting or viral-interfering substances arereferred to as interferons. They are a heterogeneous group of antiviralproteins which vary quite widely in their molecular weights. Althoughsuch proteins may differ in their physico-chemical. properties, they allexhibit the same biological properties; namely, they inhibit a widerange of unrelated viruses, hav no toxic or other deleterious effects oncells, and are species-specific (Lockart,. Frontiers of Biology, Vol. 2,Interferons," edited by Fintner, W. B. Saunder Company, Philadelphia,1966, pp. l9-20).

This discovery, by Isaacs and Lindenmann, in 1957 (Proc. Roy. Soc. B.147, 258-267) gave rise to great optimism that an economic preparationof exogeneous interferon might be developed for routine clinical useagainst viral infections. However, despite great expenditures of effortand money, no safe, effective, economical source has yet been developed.An alternate approach to producing interferon has, therefore, beenpursued. This approach comprises administering to the animal to beprotected, or treated, a non-viral substance which stimulates-orinduces-production of interferon in the cells. The interferon producedin this fashion is referred to as endogenous" interferon.

The discovery of antiviral compounds is far more complicated anddifficult than is the discovery of antibacterial and antifungal agents.This is due, in part, to the close structural similarity of viruses andthe structures of certain essential cellular components such asribonucleic and deoxyribonucleic acids, and to the dif ficulty ofestablishing suitable tests for evaluating antiviral agents. However,despite these difficulties, numerous non-viral substances have beenfound capable of stimulating or inducing interferon formation inanimals. Included among such substances are bacteria, parasites,bacterial endotoxins, pyran copolymers, helenine, phytohemagglutinin,polyacrylic compounds, nucleic acids and polynucleotides. Use of theseinducers is, however, objected to for one or more reasons, e.g.,toxicity, antigenicity, infectiousness, and their routine clinical useappears remote (Zhdanov, et al., Internatl. Virol. 1, 1st Int. Congr.Virol. Helsinki 1968, S. Karger, New York, pp. -1, 1969).

More recently, 2,7-bis[ Z-(diethyIaniino )ethyoxy]- fluorene-9-onedihydrochloride, a purely synthetic material of relatively low molecularweight, has been reported to be an oral inducer of interferon in mice(Abstracts Federation Proceedings, Vol. 29, No. 2, page 635, 1970;Abstracts 2189 and 2190).

A variety of antiviral agents are described in the literature. Thesehave been summarized by Osdene in Topics in Medicinal Chemistry, editedby Rabinowit z and Myerson, lnterscience Publishers, New York, 1968,pages 141-171. For the purposes of this review, Osdene has made use ofHerrmanns definition of antiviral agent (Herrmann, et al., Proc. Soc.Exptl. Biol. Med. 103, 625, 1960); namely, an agent which can produceeither a protective or therapeutic effect to the clear detectableadvantage of the virus infected host, or'

any material that can significantly enhance antibody formation, improveantibody activity, improve nonspecific resistance, speed convalescenceor depress symptoms. This definition is of such breadth as to cover bothprophylactic and therapeutic agents. It includes substances such asinterferon, and a host of synthetic materials, such as l-adamantanamine,pyrimidines, biguanides, guanidine, pteridines to mention a few. It isnoted that such synthetic materials are antiviral agents. They are notinterferon inducers but operate by a totally different mechanism.Interferon inducers may, or course, be referred to an antiviral agents.The converse, however, is not true.

Virus infections which attack animals, including man, are normallycontagious afflictions which may spread so rapidly that they can reachexplosive proportions in relatively short periods of time. In the past,many of these epidemics have resulted in large numbers of deaths andhave been responsible for huge economic losses. Obviously a method ofreducing the incidence of these viral infections, such as the method ofthis invention, would be welcome as an addition to the armamentarium ofmedical technology.

SUMMARY OF THE INVENTION 55615 e nonioii fifacidaddifiofi salts thereofwherein; is selected from the group consisting of alkyl of from 1 to 20atoms, aralkyl, aryloxyalkyl, hydroxyalkyl of from 2 to 8 carbon atomsand R is selected from the group consisting of alkyl of from 12 to 20carbon atoms, aralkyl and aryloxyalkyl of from 12 to 24 carbon atoms andR is alkoxy of from 1 to 18 carbon atoms;

each of R and R is selected from the group consisting of hydrogen, alkyland alkoxy of from 1 to 18 carbon atoms; R and R when taken together aremethylenedioxy;

provided that the total number of carbon atoms in R", R and R is from 5to 48;

R is selected from the group consisting of hydrogen, alkyl of from 1 tocarbon atoms, hydroxyalklyl of from 2 to 8 carbon atoms,phenylcarbamoyloxyflower alkyl), w-carboxyalkanoyloxy(lower alkyl),allyl, alkanoyl of from 1 to 6 carbon atoms, alkoxy(lower alkyl),gem-di(lower alkoxy)lower alkyl, alkanaoyloxy(- lower alkyl),carbo(lower alkoxy)lower alkyl, and carboxy(lower alkyl);

R, is selected from the group consisting of hydrogen, alkyl of from 1 to8 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, carbo(loweralkoxy)lower alkyl, alkanoyloxy(lower alkyl), carboxy(lower alkyl),alkoxy(lower alkyl), phenylcarbamoyloxy(lower alkyl),w-carboxyalkanoyloxy(lower alkyl), allyl, dihydroxyalkyl of from 3 to 8carbon atoms and morpholinoethyl;

with the' proviso that no ma'r'etfiatrtws of tlie R vari ables arehydroxyalkyl;

R and R when taken together with the nitrogen to which they are attachedare morpholino;

X is selected from the group consisting of straight chain alkylene offrom 2 to 6 carbon atoms and X is selected from the group consisting ofX, phenylenedimethylene, and

m is 0 or 1, with the provisos that only one of X and X is and when X isphenylenedimethylene, m is 0;

Y is selected from the group consisting of straight chain alkylene offrom 2 to 8 carbon atoms and phenylenedimethylene;

A is selected from the group consisting of hydrogen, cyano, hydroxy,alkoxy of from 1 to 20 carbon atoms, alkanoyloxy of from 2 to 20 carbonatoms, phenylcarbamoyloxy, chloro, bromo, w-carboxyalkanoyloxy(- loweralkyl), alkanoyloxy of from 1 to 6 carbon atoms, carbo(lower alkoxy) andalkanoylthio of from 2 to 20 carbon atoms and alkylthio of from l to 20carbon atoms;

R is selected from the group consisting of hydrogen, alkyl of from I to20 carbon atoms, hydroxyalkyl of from 2 to 8 carbon atoms, (loweralkoxy)lower alkyl and R is selected from the group consisting of alkylof from 12 to 20 carbon atoms and R,; is selected from the groupconsisting of alkyl of from 1 to 20 carbon atoms and each of p and n isor an integer from 1 to 6, with the proviso that the sum ofp and n is nogreater than 6', and

Z is selected from the group consisting of w-carboxy(lower alkyl),morpholino, piperidino, piperazino, N- (w hydroxy lower alkyl)piperazinoand N-(lower alkyl)piperazino.

Of the lower alkoxy, lower alkyl and carbo(lower alkoxy)groups, thosehaving up to four carbon atoms in the alkoxy and alkyl groups arepreferred since the starting materials are readily available. The termphenylenedimethylene includes, of course, the three isomeric, that is,the 0-, the mand the pphenylenedimethylene groups.

By non-toxic acid addition salts is meant those salts which arenon-toxic at the dosages administered. The non-toxic acid additionsalts, of the abovementioned bases which may be employed are thewater-soluble and water-insoluble salts as the hydrochloride,hydrobromide, phosphate, nitrate, sulfate, ac etate,hexafluorophosphate, citrate, gluconate, benzoate, propionate, butrate,sulfosalicylate, maleate, laurate, malate, fumarate, succinate, oxalate,tartrate, amsonate (4,4'-diaminostilbene-2,2-disulfonate), pamoate (l,l'-methylene-bis-2-hydroxy-3-naphthoate), stearate,3-hydroxy-2-naphthoate, p-tolenesulfonate, picrate, lactate and suraminsalt.

In addition to the above compounds, compounds of formulae I and Ilwherein (a) the X, X and Y variables represent straight chain alkyleneradicals of up to 13 carbon atoms, or branched-chain alkylene groups of3 to l3 carbon atoms; (b) X, X and Y are arylene, e.g., phenylene,naphthylene, anthrylene, biphenylene or -(CH ),arylene-(CH ),,wherein xand y are integers from i to 4; (0) those wherein one or more ofthe Rvariables represent unsaturated alkyl radicals having from 2 to 20carbon atoms and from l to 3 double bonds; polyhydroxyalkyl; aryl(phenyl, naphthyl); aralkyl (benzyl, phenethyl, phenylpropyl);phenoxyalkyl and substituted derivatives of the aforementioned aryl,aralkyl and phenoxyalkyl wherein the substituent is in the aryl moietyand is alkyl, chloro, bromo, alkoxy or carbo (lower alkoxy); (d)compounds of formulae l and Il wherein the R groups together with thenitrogen atoms to which they are attached form a heterocyclic structurewherein the heterocyclic moiety contains from 3 to 7 carbon atoms andwherein the hetero atom is at least one of N, O, or S, such asmorpholino, thiomorpholino, piperidino, piperazino, N-lower alkylpiperazino, N-(hydroxy lower alkyl)-piperazino, pyrrolo, pyrolidino,2-(lower carbalkoxy)pyrrolidino, indolo, benzimidazolo, l-benzotriazolo,2,1,3-benzothiazole, pyrazolo, phenoxazino, azetidino; azepino;tetrazolo; an azacycloalkane such as azacyclooctadecane; 10,11-dihydro--H-dibenz[b,f]a2epino; a triazepino, e.g., 1,3,5-triazepino, andll-dibenzo[l,2,5]triazepino; (e) and compounds of formula I wherein X orX represent C=NH or C=S; (f) N-oxides of the compounds of formulae Ithrough N; (g) and compounds of formula III wherein Z is N-substitutedpiperazino wherein the substituent is carbalkoxy, acyl or --X-NR Rwherein X, R, and R, are as defined above; also combat viral infectionswhen administrated t0 vertebrate animals by the parenteral route.

One preferred group of compounds of Formula I includes those wherein Ris selected from the group consisting of alkyl of from l-20 carbonatoms, aralkyl, aryloxyalkyl, and

R is selected from the group consisting of alkyl of from 12 to 20 carbonatoms, aralkyl, aryloxyalkyl and WE CH2 wherein R" is alkoxy of from 1to 18 carbon atoms; each of R and R is hydrogen, alkyl or alkoxy of from1 to 18 carbon atoms; R and R when taken together are methylenedioxy;

R and R are each hydrogen;

in is O; and

X is phenylenedimethylene.

The compounds described herein exhibit broad spectrum activity against avariety of viruses in vivo when administered parenterally(subcutaneously, intramuscularly, intraperitoneally), intranasally(e.g., by inhalation or spray) or topically to vertebrate animals. Thisusefulness is primarily one of prophylactic rather than of therapeuticcontrol of virus infections. Although the present invention is not to beconstrued as limited by such a theory, it is possible that the compoundsof this invention function in combating viral infections by virtue oftheir ability to induce the production of endogenous interferon. They donot produce interferon in tissue culture but only in vivo and can,therefore, be considered as stimulators of host defense mechanisms.

Further, these compounds stimulate the animal body to produce interferonwhen administered alone and/or in combination with an otherwiseinactive, singlestranded ribonucleic acid, such as highly polymerizedribonucleic acid from yeast, yeast nucleic acid (Calbiochem 55712,Calbiochem, Los Angeles, Calif). Those compounds which induce interferonwhen administered alone are given at considerably lower doses when givenin combination with the single-stranded ribonucleic acid. Particularlyuseful as inducers of interferon when used alone are compounds offormula I wherein R is alkyl of from 1 to 20 carbon atoms; R is alkyl offrom 12 to 20 carbon atoms; R is hydrogen, forrnyl, alkyl or from 1 to20 carbon atoms or hydroxyalkyl of from 2 to 4 carbon atoms; R, ishydrogen or hydroxyalkyl of from 2 to 4 carbon atoms; X is alkylene offrom 3 to 6 carbon atoms or phenylenedimethylene; and m is O, with theproviso that at least one and not more than two hydroxyalkyl groups arepresent; compounds of formula I wherein R,, R R and R. are as definedimmediately above, X is C=O, m is O and X is alkylene of from 2 to 6carbon atoms; compounds of formula ll wherein A is hydroxy; Y isstraight chain alkylene of 2 to 4 carbon atoms; and R and R are alkyl offrom 12 to 20 carbon atoms; and compounds of formula Ill wherein Z isN-substituted piperazino and R and R are each alkyl. An especiallypreferred group of compounds of formula I includes those in which R, andR are each alkyl of 12 to 20 carbon atoms, R; and R are eachhydroxyethyl, X is straight chain alkylene of from 3 to 5 carbon atoms,and m is O. Particularly valuable are the following compounds:

N,N-dioctadecyl-N -formyll ,3-propanediamine,

N,N-dioctadecyl-N,N-bis(2-hydroxyethyl)-1 ,3-

propanediamine, 1-dioctadecylaminomethyl-3-aminomethylbenzene,

butanediamine,

N,N-dioctadecyl-N,N-bis(2-hydroxypropyl)-l,3-

propanediamine,

N-(2-hydroxyethyl)dioctadecylamine,

N-(3-hydroxypropyl)dioctadecylamine,

l,l-dioctadecyl-3-(2-[bis(2-hydroxyethyl)amino]ethyl)urea,l-(N,N-dioctadecylcarbamoyl)-4-methylpiperazine,1(N,N-dioctadecylcarbamoyl)-4-(2-hydroxyethyl)- piperazine.

The compounds of this invention, many of which are known, are preparedby methods familiar to those skilled in the art.

vU.S. Pat. No. 3,235,501, for example, discloses, in theory at leastwhen all combinations and permutations of the several variables areconsidered, thousands upon thousands of polyoxyalkylated aliphaticamines derived from primary and secondary monoand diamines. Thecompounds are produced by alkoxylation (etnoxylation or propoxylation)of primary and secondary monoand diamines. In such cases, thealkoxylation reaction occurs in a random manner to produce a mixture ofalkoxylated compounds in which from 1 to 25 alkylene oxide moieties maybe present. Many of the compounds of formula I above fall within thetheoretical list of compounds encompassed by this patent. However,despite the extremely broad, indeed infinite, disclosure to polyoxylatedaliphatic amines, the patent is completely devoid of reference tospecific compounds embraced by formula 1 above. The innumerablepossibilities of the patent disclosure coupled with the ambiguous andvague nature of the method of preparation disclosed, render it unlikelythat any specific compound would be suggested to one skilled in the art.

Also disclosed in the literature are compounds of formula Ill whereineach of R and R is hydrogen or lower alkyl (Kushner, et al.,'J. Org.Chem. 13, 133-53, 1948; Pressman, et al., J. Am. Chem. Soc. 70, 1352-8,1948). Such compounds do not induce interferon when administered toanimals as described herein. Quite unexpectedly, however, it has beenfound that when at least one of R and R is alkyl of twelve or morecarbon atoms, the compounds do function to comat viral infectrons.

The basic reaction is the alkylation of an amine, primary or secondarywith, for example, an alkyl halide or hydroxyalkyl halide, usuallychloride or bromide in an organic solvent in the presence of a base oracid acceptor. Other methods of alkylation can, of course, be employedsuch as the use of aluminum alkoxides, esters of sulfuric andp-toluenesulfonic acid. Appropriate methods for preparing compounds ofthe above formulae are described by Zook and Wagner, Synthetic OrganicChemistry, John Wiley and Sons, Inc, New York, 1953, pages 666-670.

Derivatives of 1,3-propanediamine are conveniently made bycyanoethylation of the appropriate primary or secondary amines byconventional methods. The propionitrile compound (R,R NCH CH CN) thusobtained is then hydrogenated to the corresponding 1,3- propanediamine(R,R NCH CH' CH NH by I wellknown methods, e.g., hydrogenation overRaney nickel.

I Acylated amines are readily prepared by treating the appropriate aminewith an acyl halide or anhydride in the presence of a base according toprocedures well known to those skilled in the art.

An alternative method for preparing compounds of formulae 1 and 11having N-hydroxyalkyl groups comprises treating a hydroxyalkyl reactant,e.g., an N,N- dialkylamino alkanol, with methane sulfonyl chloride andthen reacting the reaction mixture with the appropriatehydroxyalkylamine or di(hydroxyalkyl) amine.

Urea derivatives of formulae 1 and III are also prepared by conventionalmethods as by reaction of a'carbamyl chloride (R,R NCOCl) with an aminoreactant H NX-NR R, or N-substituted piperazine in an organic solvent inthe presence of an acid acceptor which can, of course, be an excess ofthe amine reactant.

Compounds of formula I wherein the x variable is phenylenedimethyleneare prepared by Standard procedures from cyanobenzylbromides orchlorides. The appropriate amine, e.g., R R NH, is benzylated with acyanobenzylbromide or chloride and the cyanobenzylamine compoundproduced reduced to the corresponding aminomethylbenzylamine derivative.The a'minomethyl group (-CH NH is then treated, e.g., alkylated, withappropriate reactants to convert it to CH NR R Compounds of. formula 11wherein Y is phenylenedimethylene are also prepared by benzylation ofthe appropriate amine R R NH with a cyanobenzylbromide (or chloride).The cyanobenzylamine thus produced is converted to an ortho ester whichis reduced to an acetal and subsequently hydrolyzed to the aldehyde.Reduction of the aldehyde affords a hydroxymethyl benzylamine. Thehydroxymethylserves as convenient route viaknown procedures to formula11 compounds, and also to formula 1 compounds, e.g., by halogenation andamination.

The herein-described compounds of formulae I, II and 111 wherein the R RR R R or R groups are substituted benzyl are conveniently produced fromappropriate benzaldehydes via reduction to a benzyl alcohol followed byconversion to a benzyl chloride and then amination. Alternatively, thebenzaldehyde is reductively aminated to produce, depending upon theconditions, a monoor dibenzylamine. Utilization of the benzylaminederivatives in conventional reactions as described above affordscompounds of formulae l-III.

Acid addition salts of the compounds described herein are prepared byconventional procedures as by mixing the amine compound in a suitablesolvent with the required acid and recovering the salt by evaporation orby precipitation by addition ofa non-solvent for the salt. Hydrochloridesalts are readily prepared by passing dry hydrogen chloride through asolution of the amine compound in an organic solvent such as ether.

The antiviral activity of the above-described materials is determined bythe following procedures. In the first procedure, the test compound isadministered to mice by the intraperitoneal route 18 to 24 hours priorto challenging the mice with a lethal dose of encephalo myocarditisvirus and determining the survival rate days after challenge. Theprocedure in which the drug is given eighteen to 24 hours before and ata distinctly different site from virus injection is designed toeliminate local effects between drug and virus and select only compoundswhich produce a systemic interferon response.

The second general procedure discriminates between compounds whichexhibit antiviral activity in the first procedure for their ability toproduce an antiviral state in mice as indicated by their ability tostimulate circulating interferon after parenteral administration. Inboth procedures, the test compounds are administered alone and incombination with from about 2 to about times by weight of an otherwiseinactive (norinducer of interferon and nonantiviral), singlestranded,highly-polymerized ribonucleic acid from yeast, yeast nucleic acid.

DETAILED DESCRIPTION OF THE INVENTION Parenteral, topical and intranasaladministration of the above-described amines to an animal, includingman, before exposure of the animal to an infectious virus provide rapidresistance to the virus. The resistance engendered is non-specific andis effective against a great number of viruses. Such administration iseffective when given as much as seven days prior to exposure to thevirus. Preferably, however, administra tion should take place from aboutthree days to about one day before exposure to the virus, although thiswill vary somewhat with the particular animal species and the particularinfectious virus.

When administered parenterally the materials of this invention are usedat a level of from about 1 mg./kg. of body weight to about 250 mg./kg.of body weight. The favored range is from about 5 mg./kg. to about 100mg./kg. of body weight, and the preferred range from about 5 mg. toabout 50 mg./kg. of body weight. The dosage, of course, is dependentupon the animal being treated and the particular amine compound involvedand is to be determined by the individual responsible for itsadministration. Generally, small doses will be administered initiallywith gradual increase in dosage until the optimal dosage level isdetermined for the particular subject under treatment.

Intraperitoneal injections are the preferred method of parenteralinjection for several reasons: simplicity, convenience and the compoundsappear less toxic. Vehicles suitable for parenteral injection may beeither aqueous such as water, isotonic saline, isotonic dex trose,Ringers solution, or non-aqueous such as fatty oils of vegetable origin(cottonseed, peanut oil, corn, sesame) and other non-aqueous vehicleswhich will not interfere with the efficacy of the preparation and arenon-toxic in the volume or proportion used (glycerol, ethanol, propyleneglycol, sorbitol). Additionally, compositions suitable forextemporaneous preparation of solutions prior to administration mayadvantageously be made. Such compositions may include liquid dilvents,for example, propylene glycol, diethyl carbonate, glycerol, sorbitol.

When the materials of this invention are administered, they are mosteasily and economically used in a dispersed form in an acceptablecarrier. When it is said that this material is dispersed, it means thatthe particles may be molecular in size and held in true solution in asuitable solvent or that the particles may be colloidal in size anddispersed through a liquid phase in the form of a suspension or anemulsion. The term dispersed also means that the particles may be mixedwith and spread throughout a solid carrier so that the mixture is in theform of a powder or dust. This term is also meant to encompass mixtureswhich are suitable for use as sprays, including solutions, suspensionsor emulsions of the agents of this invention.

In practicing the intranasal route of administration of this inventionany practical method can be used to contact the inducer with therespiratory tract of the animal. Effective methods includeadministration of the inducer by intranasal or nasopharyngeal drops andby inhalation as delivered by a nebulizer or an aerosol. Such methods ofadministration are of practical importance because they provide an easy,safe and efficient method of practicing this invention. For intranasaladministration of the inducer, usually in an acceptable carrier, aconcentration ofinducer between 1.0 mg./ml. and mg./ml. is satisfactory.Concentrations in the range of about 30 to 50 mg./ml. allowadministration of a convenient volume of material.

For topical application the inducers are most conveniently used in anacceptable carrier to permit ease and control of application and betterabsorption. Here also concentrations in the range of from about 1.0mg./ml. to about 250 mg./ml. are satisfactory. In general, in the abovetwo methods of administration a dose within the range of about 1.0mg./kg. to about 250 mg./kg. of body weight and, preferably, from about5.0 mg./kg. to about 50 mlg./kg. of body weight will be administered.

The compounds employed in this invention may be employed alone, i.e.,without other medicinals, as mixtures of more than one of theherein-described compounds or in combination with other medicinalagents, such as analgesics, anesthetics, antiseptics, decongestants,antibiotics, vaccines, buffering agents and inorganic salts, to afforddesirable pharmacological properties. Further, they may be administeredin combination with hyaluronidase to avoid or, at least, to minimizelocal irritation and to increase the rate of absorption of the compound.Hyaluronidase levels of at least about (U.S.P.) units are effective inthis respect although higher or lower levels can, of course, be used.

Those materials of this invention which are waterinsoluble, includingthose which are of low and/or difficult solubility in water, are, foroptimum results, administered in formulations, e.g., suspensions,emulsions, whichpermit formationof particle sizes of less than about20p. The particle sizes of the formulations influence their biologicalactivity apparently through better absorption of the active materials.In formulating these materials various surface active agents andprotective colloids are used. Suitable surface active agents are thepartial esters of common fatty acids, such as lauric, oleic, stearic,with hexitol anhydrides derived from sorbitol, and the polyoxyethylenederivatives of such ester products. Such products 1 l are sold under thetrademarks Spans and "Tweensf respectively. and are available from theAtlas Powder Co., Wilmington, Del. Cellulose ethers, especiallycellulose methyl ether (Methocel, available from the Dow Chemical Co..Midland, Mich.) are highly efficient as protective colloids for use inemulsions containing the materials of this invention.

The water-soluble materials described herein are ad ministered foroptimum results in aqueous solution.

The production of interferon by the administration of compoundsdescribed herein is demonstrated by the protection of animals, generallymice as the initial test animal, against viral infections.Encephalomyocarditis virus is a convenient test organism. The challengevirus is prepared by inoculating mice for at least five passages with aneurotropic strain of encephalomyocarditis virus (infected mouse brain).A 10 percent suspension of infected brain tissues is prepared frominfected mice and stored at 70 C. until needed (Takano, et al., J. Bact.90, 1542, 1965). It is titrated to a dose which will cause death in 5 to7 days after challenge to unprotected animals. It is givensubcutaneously into the neck scruff. The appropriate dose is containedin 0.1 ml. In general, the dose administered to the animals is from 10to 25 times the LD (the dose which causes the death of 50 percent of theanimals).

For determination of antiviral activity, mice are parenterally(intraperitoneally) injected with the test compound at levels of 5 or 10mg./kg. and 50 mg./kg. of body weight 18 to 20 hours prior to viruschallenge and the number of survivors determined 10 days afterchallenge. Interferon production is monitored following injection of thetest compound according to the procedure described by Wheelock, Proc.Soc. Exptl. Biol. Med. 124, 855-85 (1967).

Once interferon induction by a given compound is observed, the compoundis administered to the test animal at various time intervals prior tochallenge, e.g., 6, 36, 48 and 72 hours, and by other parenteral routes,e.g., intramuscular and subcutaneous.

The induction of interferon is demonstrated in the following manner. Arepresentative formulation containing N,N-dioctadecyl-N,N-bis(2-hydroxyethyl)- 1,3-propanediamine as the inducer is exemplified.

A mixture of the inducer (100 mg.) and polysorbate 80 (Tween 80; 0.1ml.) is heated in a boiling water bath. The amine melts and iscompletely miscible with the polysorbate 80. To this mixture is thenadded with vigorous vortexing 2.5 ml. ofthe following compositionpreviously warmed to about 55 C:

Q-P DOOM COCO 984.80 g. available from Hercules Powder C0,,

Mice weighing 20 to 25 grams are housed in groups of five and are givenfood and water ad libitum. The test material is evaluated at 5 mg./kg.and 50 mg./kg. of body weight and given in a single intraperitonealinjection (0.5 ml.) 18 to 20 hours prior to bleeding. The mice are bledunder ether anesthesia from the bracheal artery, the blood collected inheparinized pipettes and tubes, and the pooled plasma from the five miceprepared by centrifugation of the blood for 30 minutes at 2,000 RPM.Dilutions of the plasma are pipetted into plastic tubes containingsheets of L-929 mouse fibroblasts (available from Flow Laboratories,Rockville, Md.). These latter are 24 hour cultures in L-l5 mediacontaining 10 percent fetal calf serum and antibiotics (available fromGrand Island Biological Company, Grand Island, N.Y.). The cultures aregrown from initial plantings of 1 ml. of 100,000 cells/ml. After 24hours of incubation with the plasma, the cultures are washed with mediaand challenged with 0.2 ml of a dilution of vesicular stomatitis virustitrated to produce a complete destruction of the cell sheets in 24 to48 hours. The cultures are in contact with the virus dilution inprotein-free media for one hour to allow the virus to adsorb to thecells and then the tubes receive 1 ml. of complete media. After 24 to 48hours of incubation at 37 C., the tubesv are scoredfor cytopathogenieeffect of the virus and compared with standard interferon samples.Interferon units are recorded as the reciprocal of the plasmaconcentration which affords 50 percent protection to the cell sheets.

The antiviral activity of N,N-dioctadecyl-N,N'-bis(2-hydroxyethyl)-l,3-propanediamine is determined using female albinoSwiss mice (Charles-River) as the test animal. Mice weighing 20 to 25grams are housed in groups of five and are given food and water adlibitum. The test material is evaluated at two dose levels (5 mg./kg.and 50 mg./kg of body weight) and administered in a single 0.5 ml.intraperitoneal injection 18 to 20 hours prior to virus challenge. Onthe following day 18 to 20 hours post injection the mice are challengedsubcutaneously with an 0.2 ml. injection of encephalomyocarditis virusat a dilution titrated to give-a 5- to 6-day death endpoint inunprotected animals. Survival data is recorded for the subsequent 10days and the l0- day survival is used as an index of efficacy. Validityof each test is established by the inclusion of unprotected groups andgroups receiving pyran co-polymer, 100 mg./kg., for positive control.

The water-soluble compoundsof the invention are convenientlyadministered in phosphate buffered saline. The water-insoluble compoundsare administered in formulations of the type described above or invarious other formulations as previously noted. Dimethysulfoxide servesas a suitable vehicle for waterinsoluble compounds. A representativeformulation for such compounds comprises 25 to 100 mg. of the chosendrug, dime'thylsulfoxide (1 ml.), polysorbate 80 (1 ml.) and 8 ml. of acomposition comprising Methocel-lS 0.50 g./l Polysorbate 80 1.00 g./lCMC- 10.00 g./l Sodium chloride 9.00 g./l. Methyl p-hydroxybenzoate 1.80g./l. Propyl p-hydroxybenzoate 0.20 g./l. Distilled water 984.00 g./l.

In certain instances, as where clumping of the drug particles occurs,sonication is employed to provide a homogeneous system.

EXAMPLE I N,N-Dioctadecyl-N,N'-Bis (2-Hydroxyethyl)-l,3-

Propanediamine A mixture of octadecylbromide (666 g., 2.0 moles),N-(3-aminopropyl)-diethanolamine (162 g., 1.0 mole) and potassiumcarbonate (276 g., 2.0 moles) is stirred vigorously and heated slowly to120C. and held at this temperature for one-half hour. The mixture isallowed to cool to 70C. then 500 ml. ofa 1:1 methylene chloride-watermixture added. The mixture is then slowly poured into a stirred mixtureof methylene chloride (9.75 liters)-water (9.75 liters). The methylenechloride phase is separated after 15 minutes and the remaining aqueousphase extracted with methylene chloride (4 liters). The combinedmethylene chloride extracts are dried over anhydrous magnesium sulfatethen stripped to one-half volume under reduced pressure. The concentrateis then stirred with silicic acid (300 g.) for one-halthour. the silicicacid removed and the clear solution slowing poured into acetone (16liters) containing succinic acid (300 g.). The mixture is cooled slowlyto C. and the succinate salt filtered off; 615 g. (68 percent oftheory); m.p. 7890C.

It is purified by recrystallization from acetonemethylene chloride (21The free baseis obtained by dissolving the succinate salt (420 g.) inmethylene chloride (4 liters) and aqueous sodium hydroxide (2.5 litersofS percent solution). The mixture is stirred for minutes, the methylenechloride phase separated and washed successively with aqueous sodiumhydroxide (1 X 18 liters of 5 percent solution), water (3 X 6 liters)and saturated aqueous sodium chloride (1 X 6 liters). It is then dried(MgSO,), filtered and evaporated in vacuo to the oil. The oil isdissolved in acetone (5 liters) at 50C. and the solution allowed to coolslowly to give a white precipitate (267 g.) m.p. 394lC. Anotherpreparation yielded a somewhat lower melting point of 36-36.8C.

Additional product (20 g.) is obtained by cooling the filtrate to 0C.Total yield is 287 g.; 43 percent of theory.

Elemental analysis infra-red (1% in KBr) Major absorption maxima (inmicrons) at: 3.05, 3.43 3.52, 6.80, 7.15, 7.25,

The dilactate salt is prepared by adding two equivalents of lactic aciddissolved in ether to an ether solution of the base, followed byevaporation of the ether; m.p. 50-52 C. becomes tacky and melts at 62 C.

The diphosphate salt is prepared by adding excess phosphoric acid to asolution of the base in hexane. It is recrystallized from a large volumeof methanol; m.p. becomes a gel at C.; brown at 190C. and melts at245247 C.

The dihydrochloride salt is prepared by bubbling dry hydrogen calorideinto an ether solution of the base. The residue obtained by removal ofthe ether is slurried in acetone, filtered, and recrystallized fromether containing some methanol; m.p. gels at 180-182 C. and meltscompletely at 238-240C.

EXAMPLE ll N.N-Dioctadecyl-N'.N'-Bis(2-Hydroxyethyl)E thanediamine Amixture of octadecylbromide (6.66 g., 0.02 mole),N-(Z-aminoethyl)-diethano1amine (1.48 g., 0.0lmo1e) and potassiumcarbonate (2.76 g., 0.02 mole) is heated at reflux under an atmosphereof nitrogen for 2 hours. The reaction mixture is then cooled and treatedwith aqueous sodium hydroxide (50 ml. of 10 percent solution). Ethylacetate (50 ml.) is added, the mixture thoroughly agitated and theethylacetace separated, washed with water, and dried over anhydrousmagnesium sulfate. Removal of the solvent by evaporation affords thecrude product which is recrystallized from ethylacetate or acetone; m.p.33-34 C.

The hydrochloride, phosphate, succinate and pierate salts are made byadding the above base to ethylacetate containing stochiometric amountsof the respective acids. The salts are recovered by filtration,, washedwith cold ethylacetate, and dried.

Salt M.P. (C.)

dihydrochloride 228-30 diphosphate 102-3 disuccinatc 155-6 dipicrate84-6 7 Repetition of the above procedure but usingthe appropriate(Z-hydroxyalkyl)alkanediamine derivative 7.65, 8.32, 8.39, 8.68, 9.15,9.24, and the appropriate alkyl bromide produces the follow- 9.30. 9.62,9.70, 11.04. 13.96. ing compounds:

R 11 l N (caw m 11 R, R. R, R, 11 Salt M.P. (C.;

(3.11.... C,,-,H,,, CH2CH2OH CH CH OH 2 2H,,P0, 1 33-5 CH. .CH.,OHC,,H,, C nt-, CH CH OH 2 2HBr 236-8 C,,,H.,. CH CH OH CH CH OH 3 3&45(3,11,, CH CH OH CH CH OH 2 2HC1 188-9 -Continued 1 R2 RH R. n slurM.P'fr c') .11., c rt cni cn on CH2CH2O'H "'2 ZHHPO. 221m m c cn cn oncmcmon 4 51-2 irart m aa 2 CHCH2OH 4 44 5 c u c rt... cn cn on CHQCHZOH4 39 o n... cn.r:it. o cn.c- 3 2HCI 167-170 C H c t-1 g CH CH -O-CH C- 3ZHCI 174-7 c n. c n 2CTH2CH2OCH2C- 3 2HC1 l70l C,,.H:,T c n cincmoH CHCH Ol-l 5 32-3 CWHM c,.,n, cn cn on cH cnpn 6 49-50 I EXAMPTQE Ill 5 Inlike nian n erft he following compounds are pre-N,N-Dioctadecyl-1,3-Propanediamine A. A Z-gallon autoclave is chargedwith 3-(dioctadecylamino)propionitrile (100 g.), ethanol (3750 ml.)containing anhydrous ammonia (100 g.) and Raney nickel (20 g. dry basis)and purged with nitrogen, then with hydrogen. It is then sealed and thehydrogen pressure raised to 250 psi. The autoclave is agitated, thetemperature raised to 70 C. and the mixture held at this temperature for1.5 hours at which timehydrogen absorption has ceased. The autoclave iscooled to 20 C.,'vented, and the contents removed. The catalyst isfiltered off, washed with ethanol, and the combined washings andreaction mixture concentrated in vacuo to a viscous green-yellow oil (82g.) which solidified upon standing; m.p. 3941 C.

14.17; N, 4.44 percent 14.17; N, 4.79 percent.

3-(Dioctadecylamino)propionitrile is prepared by refluxing a mixture ofdioctadecylamine (200 g.) and acrylonitrile (1903.8 ml.) for 18 hours.The mixture is then concentrated to a waxy semi-solid which is slurriedin acetone, filtered, and air dried overnight.

B. The monacyl derivatives of N,N-dioctadecyl-1,3- propanediamine areprepared as follows:

To a solution of methylene chloride (500 ml. per 0.1 mole of reactants)containing equimolar amounts of N,N-dioctadecyl-l.3-propanediame andtriethylamine and cooled in an ice-bath is added an equimolar amount ofthe appropriate acyl chloride in methylene chloride (25 ml. per 0.1 moleof acyl chloride) overa period of 15 minutes. The mixture is stirred for10 min-' utes then brought to room temperature and stirred for 1 hour.The methylene chloride phase is separated and extracted with water (3 X25 ml.). The water extract is in turn extracted with methylene chloride(2 X 25 ml.) and the combined methylene chloride phases dried (Na SO.,)then evaporated under reduced pressure. The residue is taken up inbenzene and the solution passed through a silica gel column. The columnis eluted with benzene, then with benzene containing increasing amountsof ethyl acetate; e.g., 5, 10, 25, and 50 percent. The eluate issubjected to thin layer chromatography (ethyl acetate) and thosefractions which show only one spot, combined and evaporated.

The following are thus prepared:

N-acetyl derivative M.P. 5052C.

N-propionyl derivative M.P. 48 .5-49C.

pared from appropriate reactants:

C. Formyl derivatives are prepared as follows:

N,N-dioctadecyl-N -formyl-l ,3-propanediamine A mixture ofN,N-dioctadecyl-1,3-propanediamine (4.88 g.), ethanol (l5ml.) and methylformate (35 ml.) is heated at reflux for one-half hour. By-productmethanol is distilled off and additional methyl formate (20 ml.) added.The mixture is refluxed for a half hour and allowed to stand overnight.It is taken to dryness under reduced pressure and the white solidresidue recrystallized from ethyl acetate. Yield quantitative: m.p. 4246C.

EXAMPLE IV N-(2-Hydroxyethyl)-N,N'-Dioctadecyl-1,3- Propanediamine To astirred solution of N,N-dioctadecyl-3- aminopropanol (1.16 g.. 2 mM.) inchloroform (30 ml.) is added methanesulfonyl chloride (0.285 g., 2.5mM.) and the mixture stirred for minutes. Ethanolamine (1.22 g., 20 mM.)is added and the mixture refluxed for 45 minutes, then cooled anddiluted with chloroform (200 ml.). The chloroform solution is washedsuccessively with aqueous sodium hydroxide (5 percent), water andsaturated aqueous sodium chloride. it is then dried (Na SO andconcentrated to a waxy solid. Picrate Salt: The free base is dissolvedin ethanol m1.) and a solution of picric acid (2 g.) in ethanol (20 ml.)added. The salt precipitates upon chilling the solution. lt is filteredoff, washed with cold ethanol and dried, 1.2 g., m.p. 149-151 C.Recrystallization from hot ethanol raises the melting point to 150l52 C.

In like manner, the following compounds are prepared using appropriatereactants (HNR R in place of ethanolamine. The hydrochloride salts areprepared by bubbling excess dry hydrogen chloride gas into a chloroformsolution of the free base and the salt recovered by evaporation of thesolvent.

N CH CH CH N l8 37 u R R Salt M.P. (C.)

H C H CH CH OH picrate 121-2 H CH CH(OH)CH OH picrate 39-41 H 11-C H Hicrate 64-6 H 11 C31 HCI 119-22 H n-C H, HCI 53-7 H C H CH OCH HCI 96-9H C H CH OC H HCI 90-4 H CH CH(OCH3)-.- HCI 83-8 H (CH N(CH CH OHpicrate 1 16-8 H (CH NH(CH CHOHCH;iDiCratc 105-10 H CHgCHOHCH2 (C2 5)2HCI 1 -7 C H,-, C- H picrate 108-10 |1C ,H,, n-C H,, pier-ate 66-7 CH CHCH OH picrate 80-2 n-C H,, CH CH OH picratc 48-52 CH CHOHCH, CH CHOHCH(an oil) CH CHOHCH HCI 52-4; 3 98-101 H CHgCHz-HlUFPhUllHQ 55-67, 90 HCH CH morpholino HCI 137 H CH(CH=;)CH COOC H HCI 56-79 H (CH -OH 34-345H (CH -OH picratc 84-6; 94 H (CH2l5 OH 35-6 H (CH =,OH picrate 65-70;85-90 C H CH CH OH picrate 80-6 CH (CH OH 91-4 CH COOH CH COOH 75-90 CHCOOCH', CH COOCH 75-7 (CHmOl-l (CHM- OH 41-3 (CH MOH (CHmOH picrate91-5; 100-5 EXAMPLE V N.N-Dioctadecyl-N,N'-Diallyl-1,3-propanediamine Aslurry of N,N-dioctadecyl-l,3-propanediamine (2.895 g., 5 mM.), allylbromide (4.3 ml., 50 mM), potassium carbonate (2.0 g.) and methylenechloride (10 ml.) is stirred at room temperature for 3 hours. Themixture is then cooled in an ice-bath, filtered, and the filtratechromatographed on acid-washed silica gel.

The product is eluted with 5 percent methanol-95 per- E2 CH CH OH (CH MOH (CH OH (CH MOH I A solution of octadecyl bromide (26.65 g., mM.N-(3-aminopropyl)diethanolamine g., 640 mM.) and benzyl alcohol ml.) isheated at C. for 23 hours. The benzyl alcohol is removed in vacuo (0.1mm. Hg, and 75C.) and the residue taken up in methylene chloride (250ml.). The methylene chloride solution is washed with aqueous sodiumhydroxide (1N) then with brine. It is dried (Na SO concentrated, anddistilled; b.p. 242-246C. at 0.1 mm Hg. The product is a waxy solid.

EXAMPLE VII cyl-l ,3-Propanediamine A mixture ofN,N-bis(2-hydroxyethyI)-N-octadecyl- 1,3-propanediamine (500 mg., 1.2mM.), n-butyl bromide (164 mg., 1.2 mM.) and potassium carbonate mg..1.2 mM.) is heated at 100C. for 2 hours then at 130C. for 2 more hours.The mixture is cooled. taken up in chloroform 100 ml.) and thechloroform solution washed successively with 5 percent aqueous sodiumhydroxide (100 ml.), water and brine, then dried (Na SO Removal of thechloroform provides the free base (540 mg.).

The picrate salt, prepared by the procedure of Example IV, melts at8587C.

In like manner,N,N-bis(2hydroxyethyl)-N-npropyl)-N-octadecyl-l,3-propanediamine isprepared from n-propylbromide. Its picrate salt melts at 105-106C. Thefollowing compounds and their picrate salts are prepared in like mannerby alkylation of the products of Examples 1V and V1 with the appropriatereactant:

l N (CH )n N 3 Ba R2 E 11 (cu moa 018E137 CH3 3 (ca moa c a 0 a 3 (cahoa 0 CH3 '3 Replacement of palmitoyl chloride by acetyl chlorideproduces N,N-dioctadecyl-N, N-bis(2-acetyloxyethyl)-l,3-propanediamine.its hydrochloride salt prepared by standard methods melts at l03-7C.

Repetition of this procedure but using the appropriate acid chloride inplace of palmitoyl chloride produces the following compounds:

:" 4 co R N (CH N (CH)-O-CO-R R'. n s R IH ZW Ht -Tl 3 2 S H m nr m a 3Z C2H5 IN TIT IH IH 2 2 IS UI m nr ur a 2 2 CH1 G III IIi II 3 2 I 3I lil-i IS K 3 2 II 7 m ar is m 3 3 z s m m w u 3 3 m m IR IU IH K 4 2 IT QGIN IKT lfl -3 6 2 IS IH m ar lR fl 3 8 CH3 m ur rs a 3 8 H fB andthemixture heated to reflux for one hour. The mix EXAMPLE XI ture iscooled, then taken to dryness under reduced pressure. The residue istriturated with carbon tetral,l Dioctadecyl-3-{2-[Bis(2-Hydroxyethyl)chloride, filtered, and the filtrate evaporated to dry- Amino]Ethyl}Ureaness. Ethyl acetate (25 ml.) is then added, the mixture cooled,filtered, washed with ethylacetate and dried in vacuo; m.p. 54-6C.

The following compounds are prepared from appropriate reactants by thisprocedure:

-0 CO-NHQCH A mixture ofN,N-dioctadecylcarbamyl chloride (2.9 g),N,N-bis-(Z-hydroxyethyh-1,2-ethanediamine (4.0 g.) and benzene ml.) isrefluxed and stirred for 3 hours. The mixture is then cooled,concentrated in vacuo and the residue taken up on chloroform (100 R (CHN (CH N R (Cl-.1 O CO NH 0 H R R 'n" S'" CIRHIIT CIRHK'F 3 3 lli lL'llfi llil 3 2 'zo 4i 2n -u 3 2 CHHQED HHZH 3 2 CIHHIW CINHHT 3 3 emu...om... 8 CIRHIIT CINHZU 3 6 CH C 37 3 3 CH C 3 6 CH C H 3 4 CIHHM CIR 3T4 2 Cali... cum. 2 2

KH37 H1 3? 6 2 EXAMPLE x ml.). The chloroform solution is washedsuccessively with water (2 X 50 ml.), aqueous sodium hydroxide (l XQ.t-.1 l)...and.watertlkiiQ. hen dri (Na SO4). Removal of the chloroformin vacuo leaves the crude product as an oil (3.3 g.).

It is purified by chromatography on silica gel and elution withethylacetate.

The hydrochloride salt is obtained by dissolving the purified product(0.75 g.) in ether (30 ml.) and bubbling in dry hydrogen chloride gas.Concentration of the ether provides the salt; 0.55 g., m.p. l52-153C.

The N,N-dioctadecylcarbamyl chloride is prepared by bubbling phosgeneinto a solution of N,N- dioctadecylamine g.) in chloroform (1.2 liters)at room temperature for 3 hours. The mixture is stirred for 2 hours,then filtered. The filtrate is evaporated to provide the product butsubstituting EXAMPLE xn N-(2-Hydroxyethyl)Octadecylamine A mixtureofoctadecyl bromide (6.66 g., 0.02 mole), ethanolamine (0.61 g., 0.01mole), potassium carbonate (4.14 g., 0.03 mole) and benzyl alcohol (4ml.) is heated overnight at 135-l45C. The mixture is cooled,

C H treated with eth lacetate (50 ml.) and 10 percenta ue- 18 37 0 3, yq

n y ous sodium hydroxide (10 ml.) The ethylacetate layer N c NH (Cl-I -1N 1 is separated, washed with water, and dried (Na SO 4 0 Removal of theorganic solvents under reduced pres- C H R sure gives an oil residuewhich solidifies u on coolin 1837 h 1' 'fdb h h l 'hhl V I V I t1s purl1e y c romatograp y on a umma wit 0 o- R4 m m M (ac) roform as eluant.Its hydrobromide salt is prepared by CHZCHZOH CHzCHzOH I 3 1 5 gddinhydrogen lb7rggnilcl7e3 t)3 an ethanol solution of the CH3 C l 2 HCl71-4 2156. t me is at CH CH OH CH-CH OH 1 5 HC] l20-3 I H 2 2 Z Z O 604The compounds tabulated below are prepared from CHzCHgOH CH CH OH 0 4the appropriate reactants A-Y-Br and H-NR R by the H CH CH oci-r 0 44-5CH CH OH CHZCHZOH 1 2 HC] 152-3 above procedure H CH2CH2COOH O 77-81 20I H H 0 6l-2 R q CH d CH -O-CH- o 42-4 A Y N 5 Y A" R}, R. Salt MP. (C.)

(CH2) 1 OH C H C H HBr 78-82 (gg2)3 0: gmfim gmgar 3 2 2)Zl O I l 17 l.17 1 12;.- g 93H; 5.33.1 .1 6 -(CH:): CN cling; CEIIHZ; Y HCl 73-74(CH2)2 OH C H C H 35-37 (CH2)2 OH R .1 ix ar H 74-78 -(CH2)2 OCOCHH C HC H 32-35 2)2 2 5 H .7 M BT --(CH2) OCONHC H -I' C H C H 197-198 -25???2L0 I a m mg!" 5 -CHZ Z- 0c0cH.-."" QZHZ; KHZ; (a 650 -(CHz)-1 CNW C H H84-85 Prepared by cyanoclhylation procedure of Vogel ct J.(.S. 5 I449(i952).

The compounds listed b elo w are prepaied'"'i'i1"m manner from theappropriate reactants.

*Prepared from the corre sp amples Vlll-X.

ending hydroxyalkyl compounds of this example the reactions of thecompounds listed below:

EXAMPLE XIV N,N-Dioctadecylsuccinamate Dioctadecylamine (5.21 g., 0.01mole) and succinic anhydride (0.50 g., 0.005 mole) are heated overnightat 105C. on an oil bath. The mixture is poured over ice and the solidwhich forms separated by filtration: 4.9 g.; m.p. 5762C. It is dissolvedin chloroform (50 ml.) and the solution extracted with 6Nhydrochloricacid (3 X 50 ml.). (The solid which formed at the interfaceis removed by filtration).

The chloroform phase is separated, washed with saturated aqueoussolution carbonate (3 X 50 ml.) and the emulsion which forms allowed toseparate overnight. The chloroform layer is separated, dried (Na SO andconcentrated in vacuo to an oil. Trituration of the oil with acetoneproduces a brown solid; 2.03 g.; mp. 52- 58C. Recrystallization fromethyl acetate raises the melting point to 77-8lC.

The following compounds are made from appropriate reactants (anhydridesand amines) by this procedure:

27 28 EXAMPLE XV half hour, then treated with an ethanolic solution ofsodium hydroxide (0.4 g., 0.01 mole) and refluxed for 5 N-3-Dd l ldth ldN-3- g g Egg 3:55 :33;g gi ggg xfii an more mmutes. The mixture iscooled, filtered and the A mixture of bmmoethanol (250 Q05 mole) ehtanolremoved by evaporation. The benzyl alcohol is dodecyloxy l pmpylamine(243 g 6 mole) a 5 then removed by distillation in vacuo and the residueethancl (20 m1) is heated at reflux Overnight. The SOL chromatographedon silica using first ether then methavent is removed by evaporation,the residue slurried in Q as eluams Thehhsired product is cohtained inthe hot water (20 mm and made Strongly alkaline with methanol eluate. It1s isolated by evaporation of the soltassium hydroxide. The basicmixture is extracted with vent -P- 530440 Its hydrochloride Salt meltsat ether (3 X 50 ml.), the ethereal extracts dried (MgSO and evaporated.The crude product mixture is purified Ih hke manner, the followingcompohrfds are P by chromatography on alumina. Using ether as eluantpared from the approphate reactants: A 2- removes the least polarimpurity; elution with methanol Cl and removes the diethanolamine first,then the monoethal5 nolamme derivative. H Wm,

These two products appear as blue and yellow spots, respectively, whensubjected to thin layer chromatog- 3 N raphy on a silica plate withmethanol as eluant and 2 n R iodoplatinic spray as developer. v 6

A v n "R, i R Sult "MIPICCU" IN IIT 3 CHgCH OH H C,,.H;,1 3' CH2CH2OC2H5H 155-7 m mi 3 CHZCHQOH H "H33 3 CH2CH2OH CHZCHQOH HCl l29-30 4H2 3CHgCHzOH CHgCHgOH 30-] 4H2 3 CH2CH2OH CHQCHQOH HCl 72 (dcc.) C "H33 2 25 C2H5 175-8 (0.3 mm.) m nr 2 2 5 2 s l (0.2 mm.) C H 2 (,H C2H5 (0.2mm.) m nr 2 CZH5 HC] 102- 4 m :i7 2 (C 2)3 (C' |H5)- g H ZHCl Themonoethanolamine derivatives boils at I 7 EXAMPLE XVIl l60-l66 C. at 0.3mm. mercury. v V V g H h g The following compounds are prepared in likeman- Following the procedures of Examples XV and XVI her from appropritereactants: AO-(CH ),,NH 40 the compounds listed below are prepared fromapproand BrR priate reactants:

I A o (on R h A'-'(CH) ---N 2 n (R a or R )v R n s ma a 2 IN RT lX 37 IHZS 3 IN IW H |2 25 3 IM KT I8 37 B S 3 IO ZI IO 2I 2 5 6 IH HT I IB 31lH -TF 3 IH TT H IX IH 3 lH -17 IB -TI' IX JT 3 IH R'I l8 -3T G L'R 3lli iL'l IG IL'I IE IIH 2 IZ ZS IZ Z') 6 3. 2 H 2 25 II 6 IH BT IX IIT An R, R, Salt MP. 00) v 32 2 2 2 CH; CH; CHJ l65-7 R chm: 3 CH; H Hi210-1 3 9 m m 3 CHQCHQOH H HE! R V A if R" "'"R" M R" EXAMPLE XVI W M 3m 11 H H C H O 3 3 oc,H 4-oc,,H H N-(3-Dodecylth1opropyl)DiethanolammeCINHMO 3 1 iz .1 c u o 3 4,5 0 CH, o 243 a, A mixture of3-octadecylthiopropyl chloride (3.35 g., W W 3 4OCH8H" H 0.01 mole),diethanolamine (2.1 g., 0.02 mole) and 2 5 443cm H CHHMO 2 3-OCHH 4OC HH benzyl alcohol (5 ml.) is heated under reflux for one- C H O 3 4-0C,H,, 4 0C H, H

EXAMPLE XVIII N- 2-Dodecanoylthioethyl )Diethylamine Decanoyl chloride(1.90 g., 0.01 mole) in ether (250 ml.) is added to a mixture ofdiethylaminoethanoethiol (1.33 g., 0.01 mole) and triethylamine (1.01g., 0.01 mole) in ether (250 ml.) .and the reaction mixture stirredovernight at room temperature. The white precipitate is filtered off andthe filtrate evaporated in vacuo to provide the product.

In like manner, N-(2-dodecanoyloxyethyl)diethylamine is prepared fromdecanoyl chloride and diethylaminoethanol. It boils at 103-l06C. at 0.05mm. mercury.

The following compounds are likewise prepared from appropriate reactantsby this procedure:

EXAMPLE XIX Ethyl 4-Dioctadecylaminobutyrute A solution ofdioctadccylamine (5.2 g., 0.01 mole), 5 ethyl 4-bromobutyrate (1.95 g.,0.01 mole) andtoluene (50 ml.) is heated at reflux for sixteen hours,then cooled and concentrated in vacuo to a semisolid oil. The oil istriturated with ethylacetate, filtered, and the filtrate washed withwater, then dried (Na SO Removal of the solvent gives the product as anoil (3.7 g.). It is purified by chromatography on silica gel and elutionof the column first with benzene, then with benzene containing 20percent ethylacetate. The residue obtained by evaporation of thebenzene-20 percent ethylacetate solvent is taken up in ethylacetate andconverted to the hydrochloride salt by bubbling dry hydrogen chloridethrough the solution. Concentration of the mixture in vacuo provides acrystalline material; m.p. 98-101C.

Substitution of ethyl 4-bromobutyrate by the appropriate lower alkylw-bromoalkanoate in the above procedure produces the followingcompounds:

5 A Y N A Y R R. Salt M.P.(C.)

cooc n CH2 WHM iu rn 40 Z S H2). can, C H HCl 46-48 2 5 H.).- cam, c i-iHCl 52-53 EXAMPLE XX l-(N,N-Dioctadecylcarbamyl )-4-Methylpiperazine Amixture of l-methylpiperazine (5 ml.), N,N-

dioctadecylcarbamylchloride (5.0 g.) and benzene (50 ml.) is refluxedand stirred for 3 hours. The white precipitate of l-methylpiperazinehydrochloride is removed by filtration and the filtrate concentrated invacuo to a yellow oil (4.5 g.). The oil is then charged on a silica gelpad and eluted with benzene in ml. fractions. Fractions 10-15 arecombined, a large volume of methanol added and the white crystallinematerial which separates filtered and dried, m.p. 46-47 C.

Thefollowing compounds are prepared from the appropriate reactants (R RNCOCI and H-Z):

R 7 O n N C Z 8 R R Z C12H25 c H- butylpiperazino iz -zs C H piperidinoC|2H25 C H morpholino w m CH methylpiperazino m rn CH morpholino l8 31 CH hydroxycthylpiperazino C H C|2H25 hydroxyethylpiperazino m n: CHhydroxyethylpiperazino ia sr C H, piperazino CI2H25 |2H25 piperazino3H3: CH piperazino EXAMPLE XXlN,N-Dioctadecyl-N',N'-bis(2Hydroxyethy1)-1,3-Propanediamine-N,N'-Dioxide To a solution of N,N-dioctadecy1-N,N-bis(2-hydroxyethy1)-l,3-propanediamine (3.34 g., 5 mM.) in chloroform m1.) isadded m-chloroperbenzoic acid (2.76 g., 12 mM; of 86 percent material)in chloroform (20 ml.) dropwise. The temperature is maintained at 28 C.throughout the addition and for 1.5 hours thereafter. The mixture isthen diluted with chloroform (20 ml.) and the solution washed first with1N aqueous sodium hydroxide then with brine. It is then dried (Na;. sQlandconcentrated to an oil (2.5 g.).

The hydrochloride salt is prepared by the procedure of Example V; m.p.89-94 C., 114 c. (1.65 g. from 2.5 g. of oil).

Dissolution of the hydrochloride salt in chloroform and neutralizationwith aqueous sodium hydroxide regenerates the free base. it is recoveredby drying the chloroform layer (Na SO and evaporation of the solvent.Recrystallization from chloroform-ethylacetate provides the pure base;m.p. 95-99 C.

EXAMPLE xxm Repetition of the procedures of Example Ill-B and C,

but using the appropriate alkanediamine and acid chloride reactantsprovides the following compounds:

EXAMPLE XXIV 1 -Dodecy1-4-(Z-Hydroxyethyl)Piperazine salt melts at99,103 C.

The free base is obtained by making an aqueous solution of thehydrobromide salt strongly alkaline with sodium hydroxide and extractingthe base with chloroform. The chloroform solution is washed with water,dried (Na- 80 and evaporated. The white solid which remains melts at6567 C.

By means of the above procedure, the following com- The products of thepreceding examples are conpounds are prepared but using the appropriatealkyl' verted to their N-oxide derivatives in like manner. bromide andl-(hydroxyalkyl)piperazine reactants:

R N N (ca H H H EXAMPLE XXII R" p+1 n M.P. (degrees C.) v C,2H25 3 055-7 N.N-Dioctadecyl N N bis(2-Hydroxyethy1)-1,3- 812325 3 8 ggj figggzzg l Propanediamine N-Methonium Iodide 3 |H |2(HBrsa1t) Methyl iodide(568 mg., 4.0 mM.) is added all at C H 6 0 once to a solution ofN,N-dioctadecy1-N,N'-bis(2- E E g 8 hydroxyethy1)-1,3-propanediamine(1.334, g., 2.0 2 1 mM.) in methylene chloride (10 ml.) which is cooledCIZHZS 3 2 in an ice-bath. The mixture is stirred and allowed over 7 a4-hour period to warm to room temperature, then stirred at roomtemperature overnight. The solid resi 5 I due obtained by removal ofthechloroform is recrysta1-' R fi lized from ethylacetate; 1.35 g, m.p. 122C. 8 R" 2 33 34 i .3; e B

a-oc n P 11 a 2 o 3-oc a 4-OC6H13 a 3 o 3OC6H13 4-OC6H13 H 6 o a-oc a2-cii a-ca 3 0 4-0G l1 H a 3 0 POC 11 a H 5 0 3'OCH3 4-OC H33 H 2 04,5--0 CH 0 2-0 11 5 o 2-oc a 4-oc n 5-c a 3 o 3-oc a 4-oc n H 2 1 4-oct1 H H 2 1 2-oca 4OC H 7 5-0011 2 1 2-oc 1i 4-oc 11 5 00 a 2 1 2-OC16H334-OC16H33 5 OC l-I33 Z 2 3-OC6Hl3 4-OC6H13 H 2 2 3-oc a 400 11 H 3 2a-oc a H n 3 2 EXAMPLE XXV N,N-Bis(3,4-Dihexoxybenzyl)-N,N-Bis(2-l-lydroxyethyl l ,3-Propanecliamine A mixture of3,4-dihexoxybenzaldehyde (15.3 g., 0.05 M), sodium borohydride (1.85 g.,0.05 M) and ethanol (350 ml.) is stirred at room temperature for 1- hourand then concentrated in vacuo. The residue is dissolved in chloroform(500 ml.), the solution washed with water (4 X100 ml.), dried (Na SO andevaporated under reduced pressure to give 3,4- dihexoxybenzyl alcohol(15.0 g.) as a pale yellow oil.

Thionyl chloride (140 ml.) and 3,4-dihexoxybenzyl alcohol (14.0 g.) arecombined and stirred at room temperature for one-half hour, at whichtime gas evolu tion ceases. The mixture is refluxed for one-half hourand then distilled to remove thionyl chloride (about 100 ml.). Theresidue is poured into ice-water (250 g. of each) and the aqueoussolution extracted with chloroform (3 X100 ml.). The chloroform extractsare combined, washed successively with saturated sodium bicarbonatesolution (2 X100 ml.) and water (3 X100 ml.). It is then dried (Na SOand concentrated to give 3,4-dihexoxybenzyl chloride as a brown oil(11.7 g.).

A mixture of N-(3-aminopropyl)diethanolamine (11.3 g., 7 mM),3,4-dihexoxybenzyl chloride (4.8 g., mM) and potassium carbonate (2.07g., 15 mM) is stirred at room temperature for 16 hours and then at 130C. for 2 hours. It is cooled, benzene (50 ml.) added and the mixturefiltered. The benzene filtrate is charged onto a column and the columneluted with R E ca 2-11-CH2CH2CH2 ntcrr ca om EXAMPLE XXVI N,N-Bis( 3,4-Dihexoxybenzyl)-l ,3-Propanediamine Raney nickel (500 mg),3,4-dihexoxybenzaldehyde (6.12 g., 0.02 M) and ammonia (3.0 g., 0.177 M)in ethanol ml.) are charged into a Paar shaker and hydrogenated at 40 C.and an initial pressure of 51 psi.

When approximately 20 psi drop in hydrogen pressure is observed, about24 hours, the contents are removed with water and air dried. It is thendissolved in chloroform (75 ml. the solution washed with water (50 ml.

and filtered. The filtrate is concentrated in vacuo to an dried (Na SOand concentrated to give amber oil which is dissolved in ethyl acetate(50 ml.). bis(3,4-dihexoxybenzyl)aminc as an oil; l.4 g.. 69.8 Thesolution is treated with ethyl acetate saturated with 5 yield. hydrogenchloride 100 ml.) and the resulting white hy- Acrylonitrile (15 ml.) andhis 3,4-dihexoxybenzyldrochloride salt collected; 3.7 g., m.p. 205-206C. )amine are refluxed together for l8 hours. The mixture The salt isthen partitioned between chl r f m (100 is then cooled and concentratedin vacuo to an oil: 1.2 ml.) and saturated sodium bicarbonate solution(50 gi ml.). The chloroform phase is separated, washed with Thecyanoethyl ldeflvatlve g), hlckel water (50 ml.), dried (Na SO andconcentrated to g ammOma 8-) and ethanol are give3,4-dihexoxybenzylamine as an oil; 3.2 g., 52.1% charged into a Paarshaker and hydrogenated at room ield. tem erature and an initial ressureof 50 si. When u y I P P P P A solution of 3,4-d1hexoxybenzylamine (2.0g., 6.52 take of hydrogen is complete, the contents are removed mM),3,4-dihexoxybenzaldehyde (2.0 g., 6.52 mM), filtered and concentrated togive the title produce as an benzene (75 ml.) and p-toluenesulfonic acid(200 mg.) 011 g-)- is refl xed with ti i i apparatus i d ith a Thedihydrochloride salt is formed by dissolving the Dean-Stark collectorfor 16 hours. It is then cooled and ProduCt ether and bubbling hydrogenChloride into concentrated in vacuo to an oil which crystallizes uponthe SOIUUOII' Removal Of h ther nder reduced presstanding: 4.0 g. of theSchiff base. sure g ves the salt. n

The Schiff base is reduced by treatment with sodium Smnlarly. s p p y y)-l borohydride (03 78 ,)-i th l l per 2 f propanediamme 18 prepared bysubstituting 3,4diiso- Schiff base) at room temperature for 20 hours.The p p y yd for d y nza d hyd mixture is concentrated under reducedpressure to a 78 Its dihydrochloride salt metls at '68 C.- solid whichis taken up in methanol. Hydrogen chloride gas is bubbled into thesolution. water (50 ml.) added EXAM E and the salt filtered. washed withwater and air dried. The fOHOWIh'g N y y|)- The dry salt is dissolved inwarm methanol ml.), alkanediamin'c derivatives are prepared fromapproprisaturated aqueous sodium bicarbonate (50 ml.) and ate reactantsby the procedures of ExamplesXXV, water (50 ml.) added. The solid isfiltered off, washed 30 XVI and X I l I? 3 I R CH2 N &X N X' N\ R R R Xm X R3 V 2OC3H1 3OC2H,, H O CH2CHI CH2CH2OH CHQCHQOH 3 0CH 4-0C...H H 0-(CHZ)3 CH CH OH CH CH OH ,G 11 H H 0 (CH..).- CH Cl-l OH CH2CH2OH X2 TSl2 25 H 0 2)1 a m m 3OC H 4OC,2H2,, H O -(CH H3 m a1 r: u n m H 0 (CH2)CHZCHZ OH CH2CH2OH is n H H O (CH2)1-- (CHQGOH (CH OH P H, m :n H o-(CH2)2 C .,H H 2 OC2H 4 OC2H5 n m O (CH2)(F m 2| m -n K H H H 0 CH CH-CH=CH CH -CH=CH |1 H H CH CH l -CH CH CH CH OH cH cH oH m 37 H H -(CH2l -(CH2)3 CH2CH2OH CH CH OH fi l-'l u m H (CH2)4 l (CH2)4- CH2CH2OHCHZCHZOH C2 5 4 OC2H5 z 2)3 1 (C 2)1- iu m m M 1l nt :n 6 CH:1 *CH2CH2 lCH2CH2 (CH2).|OH (CH 2)40H .-l 4 OC|2H2: 60CH=, 0 -(c CH CHOHCH OHCHZCHOHCHZOH n r. .2 2.-, H 0 -(CH2);, CHZCHOHCHZOH CH2CHOHCH2OH 4OC|M(7 H H 0 (CH2) 1 H C1H|5 -QQH... H (CH2)=, 1 (CH CH2CHOHCH3 cH cHoHcH:IH JW 1! 6 CH:1 0 (CH2) r- CH2COOCH3 CHQCOOCHK Ha H H 0 -(CH,)CH2CH2OCHHZ5 H rx ii 3 0( 2H5 H (CH2)2 1 -(CH )g H37 CH2CH=CH2 4-()(.,.H H H (CH2)2- 1 (CH CH2CH=CH2 CH2CH%H2 N IZI u m H 0 (CH2), H i H m:n H H (CH2) 1 -(CH2)2 H H 2 u m m 6 l1l 0 (CHg)3 CHZCHZOH CHZCHZOH :"O(H:| IN IW 5 OCH.1 O (CH2)4- C H 7 CRHH 2 'OEHII 4-OC lJ LS 7-OCH3 0-(CH2);; H H 4 o( ..H.,,. H H 0 H2)2- H H 2 oc..H, 3-OC2H5 H 0 (CH2)., HH z ;12 's 4 0C2H5 H 0 (CH2),; H H 4 O(- IN I H H 0 -(CH2 1 H H 2 2 a 0(CH2).1- H H 0 (CH CH-CH OCH- CH CH H. Foetal. 2CH1, 6 cH 0 r jll H 2 =CQfi I r m H co 1 (CH CH CH OH CH Cl-l OH i' gg ff 0C H S g8 flgfinr t tH l og (CHMOH 1a i. H CHqCH OH 4 s o c H: 2C '.H CO l (CH:),, rci i i 2

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 whereinR1 is alkyl of from 6 to 20 carbon atoms; R3 and R4 are eachhydroxyalkyl of from 2 to 4 carbon atoms; X and X'' are each alkylene offrom 2 to 3 carbon atoms; and m is
 1. 3. A compound according to claim 1wherein m is
 0. 4. A compound according to claim 1 wherein R1 and R2 areeach alkyl of from 12 to 20 carbon atoms; R3 and R4 are eachhydroxyethyl; X'' is straight chain alkylene of from 3 to 5 carbonatoms; and m is
 0. 5.N,N-Dioctadecyl-N'',N''-bis(2-hydroxyethyl)-1,3-propanediamine, acompound according to claim 4 wherein R1 and R2 are each octadecyl andX'' is propylene.
 6. A compound according to claim 1 wherein R1 is alkylof from 12 to 20 carbon atoms.